The purpose of this work is to attempt to delineate some of the pharmacological and biochemical correlates of tolerance to the narcotic analgesics. Studies will be continued in order to elucidate the nature of the microsomal enzyme or enzymes which N-demethylates narcotic drugs and to attempt to correlate changes in the activity of this enzyme with changes in the sensitivity of animals and humans to the effect of narcotic drugs (tolerance and hypersensitivity). We shall also carry out experiments in order to test the hypothesis that tolerance may be an immunological phenomenon. These will involve passive transfer of serum from tolerant to non-tolerant animals within a given species and from one species to another in order to study the attenuation by such serum of the analgesic effect of narcotic drugs. We propose: 1. To investigate the factors involved in the appearance and loss of tolerance as they relate to chemical structure and to such exogenous effects as pretreatment with barbiturates, thyroxin, carcinogenic hydrocarbons, steroids, sex hormones and microsomal enzyme stimulators such as chlorcyclizine. 2. To elucidate the possible role which immunological factors play in the development of and loss of tolerance, to study the effect of thymectomy and radiomimetic drugs on the development of tolerance. 3. To correlate changes in rat liver N-demethylating enzyme or enzymes with the development of tolerance and to attempt to characterize the properties of this enzyme or group of enzymes.